medical chemistry , sar

1. Structure Activity
Relationship
Dr AKSHIL
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4. • Medicinal chemistry is a chemistry-based discipline,
involving aspects of biological, medical and
pharmaceutical sciences. It is concerned with the
invention, discovery, design, identification and
preparation of biologically active compounds, the
study of their metabolism, the interpretation of their
mode of action at the molecular level and the
construction of structure-activity relationships (SARs).

5. Structure activity relationship
(SAR)
• SAR is the relationship between the chemical or 3D
structure of a molecule and its biological activity.
• The analysis of the dependence of biological effects
of a chemical upon its molecular structure.
• Molecular structure and biological activity are
correlated by observing the results of systematic
structural modification on defined biological
endpoints.
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6. • Determination of the chemical groups responsible
for evoking a target biological effect in the
organism.
• Quantitative SARs (QSAR)as a special case of SARs
(when relationships become quantified)
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7. 7
Crude drug Structure Ligand bindingReceptor
Biological
response
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WHY SAR Exist?
• The interaction of the drug molecule with protein depends
on its chemical structure
NEED OF SAR STUDY
• A study of the structure–activity relationship is mainly
done by lead molecule.
• It is used to determine pharmacophore, unwanted side
effects
• To develop a new drug that has increased activity.
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Cont.…..
• To determine some different activity from an
existing drug
• To fewer unwanted side effects
• To know the changes in pharmacological properties
by performing minor changes in the drug molecule
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10. QSAR
• Attempts to find consistent relationship between
the variations in the values of molecular properties
& the biological activities for a series of compounds
so that these “rules” can be used to evaluate new
chemical entities.
• 3D QSAR –most powerful technique available for
analog – based drug design.
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11. History of Medicinal Chemistry
Early investigations of natural products
In the so-called pre-scientific era
• Natural products having a history as folk remedies
were in use. Fore examples, opium, belladonna,
cinchona bark, etc. Many drugs originally used as
folk remedies, nowadays, have been abandoned.

12. • In the late eighteenth and early nineteenth centuries,
chemical experimentation led ultimately to its use in
the discovery of new drugs.
• In 1853, Henry How conceived the idea that
functional groups in natural products might be
modified by chemical reagents.
He heated morphine with methyl iodide, hoping to
convert the alkaloid to codeine. He obtained, however,
a new substance of the quaternary salt of morphine.
HO O
H OH
N

13. • In 1898, the first commercially available semisynthetic
morphine derivative (ethyl ether) was introduced as a
cough sedative in preference to codeine or other
opiates.
• Meanwhile, diacetylmorphine was introduced as a
safer pain reliever than morphine. It quickly became
popular throughout the world.
• Four years passed before its addictive properties of heroin were
recognized. Laws were later passed by governments to restrict its
use.

14. • During the 1840s, the first use of synthetic organic
chemicals were introduced for anesthesia during a
tooth removal, such as nitrous oxide, ether, and
chloroform.
• In 1864, barbituric acid had been synthesized as a
useful hypnotic.

15. • In 1875, salicylic acid was introduced as a possible
cure for typhoid fever. It was found to be an effective
antipyretic.
• In 1899, Aspirin (Acetyl salicylic acid) was marketed
as an antipyretic without the unpleasant side effects.
This indicated that the chemical structures from
natural products were changed into better drugs.
• Medicinal Chemistry began.

16. Selectivity of Drug Action and
Drug Receptors
• Similar molecules exert similar biological actions in
a qualitative sense.
• Both agonists and antagonists share common
structural features.
• Composition and arrangement of chemical
functional groups, determines the type of
pharmacologic effect it possesses.
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17. Chemical compound
Lead molecule
screening
SAR studies
pruning
Pharmacophore
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18. Screening
Screening is the systematic examination of a chemical
molecule to identify the lead molecule.
Methods of screening:
1. Identification by Random screening.
2. Identification by Non-Random screening.
3. Identification by drug metabolism
studies.
4. Identification by observing side effects.
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19. Random Screening
The lead compound for the development of most drugs
is found by screening thousands of compounds
randomly
A random screen is a search for a pharmacologically
active lead compound without any information about
what structures might show activity
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20. Identification by drug metabolism studies:
azo reductase
Prontosil Sulphanilamide
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21. Identification by observing side effects:
Benzodioxanes Ethanolamines Ethylenediamine
Promethazine
Chlorpromazine
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22. Pruning:
Pruning is the refinement of lead structure.
It is done to determine the pharmacophore.
Pharmacophore:
A pharmacophore is a spatial arrangement
of functional groups essential for biological
activity. It is a pattern that emerges from a
set of molecules with a common biological
activity.
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23. A
C
D
E
Benzomorphan
Meperidine
Morphine Levorphanol
B A
B D
C
A
D
A
D
B
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24. PHYSICOCHEMICAL PROPERTIES OF
DRUGS:
• Acid-Base Properties
• Water Solubility of Drugs
• Stereochemistry
• Electronic parameters
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25. Acid-Base Properties
• Possible to predict ,if a molecule gets ionized or
unionized at a given pH simply by knowing if the
functional groups on the molecule are acidic or
basic.
• Quantitatively predict the degree of ionization of a
molecule.
• Henderson-Hassalbach equation
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27. Water Solubility of Drugs
• It Greatly affects the routes of administration.
• Two key concepts :
• 1) hydrogen bond forming(Drugs with possibility of
more hydrogen bond formation will have more
solubility)
• 2) ionization of functional groups.
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28. R
O
H
Alchohol
O
HH
H
O
H
O
H
H
3 H-Bonds
OAldehyde / ketone
HH
O
H
O
H
2 H-Bonds
R R'
OEster
HH
O
H
O
H
3 H-Bonds
R O
R
H
O
H
Ion - dipole bonds
H
N HR
H
Acidic form of amines
H
O
H
-
+
+
R
O
O
Basic form of carboxylic acid
(carboxylate)
H
O
H
+
+ -
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29. Predicting Water Solubility:
Empiric Approach
• Based on carbon- solubilising potential of several
organic functional groups.
• Solubilising potential of the functional groups
exceeds the total number of carbon atoms present,
then the molecule is considered to be water
soluble. Otherwise, its water insoluble.
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30. • Functional groups that can interact
either through intramolecular hydrogen
or ion-ion interactions will decrease the
solubilizing potential of each group.
Intramoleculare interact. reduce water sol.
R
CO2
NH3
Strong intramolec interact.
O
H H
O
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31. Predicting Water Solubility:
Analytical Approach
• PARTITION CO-EFFICIENT- It is the extent of distribution
of drug between oil phase and water phase.
• If the drug is more hydrophobic it will have high p
value and it can cross biological membranes easily.
• Partition co-effecient of a drug can be determined by
its distribution in an octanol-water mixture.
P= Concentration of drug in octanol
Concentration of drug in aqueous solution
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32. Log P =Σπ(fragments)
• Log of the partition coefficient for a molecule
Predicts Water Solubility
• Log P is the sum of the hydrophobic and
hydriophilic characteristics of the organic functional
groups making up the structure of the molecule.
• Thus, logP is a measure of the solubility
characteristics of the entire molecule.
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33. STEREOCHEMISTRY AND DRUG
ACTION
• Stereo isomers are compounds containing
the same number and kinds of atoms, the
same arrangement of bonds, but different
three-dimensional structures.
• 2 types  enantiomers and
diastereoisomers
• If functional groups are in the proper 3D
orientation, the drug can produce a very
strong interaction with its receptor.
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34. STEREOCHEMISTRY AND DRUG
ACTION
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35. • The physiochemical properties of a drug molecule
dependent on (a) functional groups in the molecule
(b)spatial arrangement of these groups.
• Enantiomers when introduced into an Asymmetric
environment(human body) ,it will display different
physiochemical properties, producing significant
differences in their pharmacokinetic and
pharmacodynamics behavior.
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36. Easson and Stedman Hypothesis
• reasoned that differences in biological activity
between enantiomers resulted from selective
reactivity of one enantiomer with its receptor.
• They postulated that such interactions require a
minimum of a three-point fit to the receptor.
(incerase potency of enantiomers)
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38. Conformational Isomerism and
Biological Activity
• dynamic process
• Isomerization takes place via rotation about one or
more single bonds.
• Neurotransmitter acetylcholine demonstrates
the concept of conformational isomers.
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39. • Rotation around the central Cα-Cβ bond produces
the greatest spatial rearrangement of atoms.
• When the ester and trimethylammonium group are
180° apart, the molecule is said to be in the anti or
staggered conformation.
• maximum separation of the functional
groupsmost stable
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40. • Rotation of one end of the Cα-Cβ bond by 120° or
240° results in the two gauche , or skew
conformations.
• Gauche conformation is the form that binds to the
nicotinic receptor
• Anti form, (achiral) binds to the muscarinic
receptor.
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42. Electronic parameters
• The electronic effects of various substituents will
clearly have an effect on a drug's ionization or
polarity.
• This in turn may have an effect on how easily a
drug can pass through cell membranes or how
strongly it can bind to a receptor.
• After drug reaching its target site distribution of
electrons in its structure will control the type of
bond between them.
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43. These SAR studies are done through Analog Approach.
ANALOG APPROACH:
1. Homologs.
2. Molecular fragmentation.
3. Addition of functional groups.
4. Isosteric Replacements.
5. Stereochemistry.
6. Ionisation.
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44. MOLECULAR FRAGMENTATION:
H
cocaine tropococaine
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45. ADDITION OF FUNCTIONAL GROUPS:
Tolazoline Naphazoline
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46. ISOSTERIC REPLACEMENTS:
1.
Uracil
5-Fluorouracil
2.
Hypoxanthine 6-mercaptopurine
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47. STEREOCHEMISTRY:
Pentobarbitol Amobarbitol
tuberculostatic
causes blindness
Ethambutol
1.
2.
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48. OH
OH
S+
Dimethylsulfonium analog
S
Permanently uncharged sulphide
I
-
IONISATION:
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Camptothecin
(CPT)
WALL & WANI in
early Sixties
Camptotheca
cuminata,Tree of Joy
Quinolino
alkaloid
Pentacyclic
ring
structure
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STRUCTURE OF CPT WITH IUPAC NAME
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A B C
D
E
Saturation of ring B< activity
necessary for activity
essential for activity, S N
inactive
D-ring pyridone is required for anti
tumor activity.
 Modifications in rings A, B are well tolerated
The stereochemistry at C-20 is very
crucial as 20(S) hydroxyl is active,
20(R) inactive
modifications at the C , D rings led
to complete loss of cytotoxicity.
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Modification in rings A,B
Topotecan
Irinotecan
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Modification in rings C,D
 In general, modifications at the C and D rings of
camptothecin led to complete loss of cytotoxicity.
 If we see these rings, the only positions available
for modifications are C-5, C-14 and C-17. Several
derivatives have been reported either with less
activity or with loss of activity.
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Modification in ring E
 The α- hydroxyl lactone system of ring E has been
found to be important for the inhibition of the
topoisomerase enzyme as well as for in vivo
potency
 Derivatives having a lactam group instead of a
lactone, were devoid of topoisomerase inhibitor
activity.
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56. Molecular Modification to Improve the Therapeutic
Properties of Cocaine
local anesthetic, but
bad effect on the
central nervous system
retains the local
anesthetic property
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57. Anesthetics Obtained through Molecular Modification
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58. Replacing the ester linkage of procaine with an amide
linkage led to procainamide hydrochloride
Active as a cardiac depressant
Active as a local anesthetic
Used clinically as an antiarrhythmic
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59. Molecular Modification of Morphine
Morphine and all the compounds prepared by molecular
modification of morphine have a structural feature in
common
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60. Molecular Modification of Codeine
Dextromethorphan is the major ingredient in most cough
medicines
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61. The tranquilizer Librium was discovered accidentally
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62. Structural modification of Librium leads to the generation
of other tranquilizers
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63. Many drugs exert their physiological effects by binding
to a specific cellular binding site called a receptor
Excess histamine in the body causes the symptoms
associated with the common cold and allergic responses
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64. Antihistamines alleviate the action of histamine by
binding to the histamine receptor
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65. 4-Methylhistamine is used as a lead compound to
develop antiulcer drugs
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66. In screening modified compounds, it is possible to find a
compound with completely different pharmacological
activity than the lead compound
e.g.
in 1942 by the chemist Marcel Janbon et al.
an antibiotic a drug with
hypoglycemic activity
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67. Molecular modification of promethazine leads to the
discovery of an antipsychotic drug
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68. Drugs as Enzyme Inhibitors
Penicillin destroys bacteria by inhibiting the enzyme that
synthesizes bacterial cell walls
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69. Antiviral Drugs
These nucleoside analogs interfere with DNA or RNA
synthesis
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70. - Quantitative structure-activity relationships
are mathematical relationships linking chemical
structure and pharmacological activity in a
quantitative manner for a series of compounds
- Biological activity can be expressed
quantitatively as the concentration of a substance
required to give a certain biological response
- When physicochemical properties or structures
are expressed by numbers, one can find a
mathematical relationship, or quantitative
structure-activity relationship, between the two
QSAR
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71. Conclusion :
• SAR deals with the influence of the functional
groups present in the drug on its biological activity
• SAR studies are done to determine the pattern of
this influence which is employed in the drug design
and in the synthesis of many drugs of desired
pharmacological activity.
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72. References:
• Medicinal Chemistry, Ashutosh Kar , 4th edi.
• Essentials of drug designing . V kothekar 1st Edition
2005
• Paul Beringer, Linda Felton et al. The Science and
Practice of Pharmacy, 21st ed, Vol.1,
• Drug design vol.10, Ariens et al.
• Goodman & gillman’s the pharmacological basis of
therapeutics, 12th edition.
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